Stefan Costinean

Publications (29)234.37 Total impact

• Article: Overexpression of miR-155 causes expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells.

  Rossana Trotta, Li Chen, Stefan Costinean, Srirama Josyula, Bethany L Mundy-Bosse, David Ciarlariello, Charlene Mao, Edward L Briercheck, Kathleen K McConnell, Anjali Mishra, Lianbo Yu, Carlo M Croce, Michael A Caligiuri
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  ABSTRACT: It now appears that microRNAs (miRs) are involved in lymphocyte development, homeostasis, activation, and occasionally malignant transformation. In this study, a miR-155 transgene (tg) was driven to be overexpressed off of the lck promoter in order to assess its effects on natural killer (NK) cell biology in vivo. MiR-155 tg mice have an increase in NK cell number with an excess of the CD11b(low)CD27(high) NK subset, indicative of a halt in terminal NK cell differentiation that proved to be intrinsic to the cell itself. The increase in NK cells results in part from improved survival in medium alone and enhanced expansion with endogenous or exogenous IL-15. Phenotypic and functional data from miR-155 tg NK cells showed constitutive activation and enhanced target cell conjugation resulting in more potent anti-tumor activity in vitro and improved survival of lymphoma bearing mice in vivo when compared to wild type NK cells. The enhanced NK cell survival, expansion, activation and tumor control resulting from overexpression of miR-155 in NK cells could be explained in part via diminished expression of the inositol phosphatase SHIP1 and increased activation of ERK and AKT. Thus, the regulation of miR-155 is important for NK cell development, homeostasis and activation.
  Blood 02/2013; · 9.90 Impact Factor
• Article: miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model.

  Sukhinder K Sandhu, Stefano Volinia, Stefan Costinean, Marco Galasso, Reid Neinast, Ramasamy Santhanam, Mark R Parthun, Danilo Perrotti, Guido Marcucci, Ramiro Garzon, Carlo M Croce
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  ABSTRACT: Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.
  Proceedings of the National Academy of Sciences 11/2012; · 9.68 Impact Factor
• Article: Primary intrathyroidal paraganglioma: histopathology and novel molecular alterations.

  Stefan Costinean, Veronica Balatti, Arianna Bottoni, Mathew Old, Carlo Croce, Paul E Wakely
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  ABSTRACT: We present the case of a 32-year-old woman with an intrathyroidal paraganglioma. Sequences of the nicotinamide NNMT (N-methyl transferase) gene at the PGL1 locus in intrathyroidal paraganglioma showed a heterozygous single nucleotide polymorphism and extragenic mutation. Also, sequences of the SDH (succinate dehydrogenase) gene subunits B, C, and D were examined and identified the presence of multiple homozygous and heterozygous single nucleotide polymorphisms. Our case confirms the presence of an increased number of single nucleotide polymorphisms and mutations in both PGL1 and SDH loci in intrathyroidal paraganglioma. To our knowledge, this is the first example of intrathyroidal paraganglioma to be so analyzed for both mutations and for single nucleotide polymorphisms in PGL1 and SDH loci. The presence of these genetic abnormalities may have therapeutic implications.
  Human pathology 10/2012; · 3.03 Impact Factor
• Article: Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.

  Shu-Hao Hsu, Bo Wang, Janaiah Kota, Jianhua Yu, Stefan Costinean, Huban Kutay, Lianbo Yu, Shoumei Bai, Krista La Perle, Raghu R Chivukula, Hsiaoyin Mao, Min Wei, K Reed Clark, Jerry R Mendell, Michael A Caligiuri, Samson T Jacob, Joshua T Mendell, Kalpana Ghoshal
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  ABSTRACT: miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
  The Journal of clinical investigation 07/2012; 122(8):2871-83. · 15.39 Impact Factor
• Article: Hepatic miR-29ab1 expression modulates chronic hepatic injury.

  Takayuki Kogure, Stefan Costinean, Irene Yan, Chiara Braconi, Carlo Croce, Tushar Patel
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  ABSTRACT: microRNAs (miRNAs) are small, regulatory noncoding RNAs that have potent effects on gene expression. Several miRNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of miR-29 in hepatic fibrosis and carcinogenesis. Although several targets of miR-29 have been identified, there is limited information regarding the cell-type specific roles of miR-29 in the liver, and we sought to evaluate the role of this miRNA in hepatic pathobiology. We report the generation of a tissue-specific knock-out mouse to evaluate the role of miR-29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that miR-29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in miR29 knockout mice in response to carbon tetrachloride. Genome-wide gene expression analysis identified an over-representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a miR-29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific miR-29 knock-out on survival following chronic hepatic injury in vivo implicates this miRNA as a potential target for intervention. These results provide evidence of the involvement of miR-29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of miR-29 in the response to hepatic injury, fibrosis and carcinogenesis. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
  Journal of Cellular and Molecular Medicine 03/2012; · 4.13 Impact Factor
• Article: Stem cell-related markers in primary breast cancers and associated metastatic lesions.

  Gulnur Guler, Serdar Balci, Stefan Costinean, Cigdem Himmetoglu Ussakli, Cigdem Irkkan, Dinc Suren, Ebru Sari, Kadri Altundag, Yavuz Ozisik, Susie Jones, Jason Bacher, Charles L Shapiro, Kay Huebner
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  ABSTRACT: It has been reported previously that: (1) normal-breast epithelial cells that are CD24-/44+ express higher levels of stem/progenitor cell-associated genes; (2) cancer cells that have undergone epithelial to mesenchymal transition display CD24-/44+ cell-surface expression, a marker for breast cancer stem cells; (3) loss of E-cadherin is a preliminary step in epithelial to mesenchymal transition; and (4) vimentin is a marker of mesenchymal phenotype. We hypothesized that stem cell subpopulations would be more frequent in metastatic than in primary tumors. Therefore we assessed by immunohistochemical analysis, tissue microarrays containing tissue from primary and associated metastatic breast cancers for expression of CD24, CD44, E-cadherin and vimentin to evaluate candidate cancer-initiating cell populations in breast cancer subtypes and metastatic lesions. The occurrence of CD24-/44+ and CD24+/44- cells did not differ in primary vs matched lymph node or distant and locoregional metastatic lesions; E-cadherin expression was decreased in primary vs lymph node metastases (P=0.018) but not decreased in distant and locoregional metastases relative to primary tumor, whereas vimentin, was more frequently expressed in lymph node and distant and locoregional metastases (P=0.013, P=0.004) than in matched primary cancers. Thus, the frequency of CD24-/44+ cells does not differ in metastases relative to the primary breast cancer but differs by tumor stage and subtype.
  Modern Pathology 03/2012; 25(7):949-55. · 4.79 Impact Factor
• Article: miR-155 regulates IFN-γ production in natural killer cells.

  Rossana Trotta, Li Chen, David Ciarlariello, Srirama Josyula, Charlene Mao, Stefan Costinean, Lianbo Yu, Jonathan P Butchar, Susheela Tridandapani, Carlo M Croce, Michael A Caligiuri
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  ABSTRACT: MicroRNAs (miRs) are small, noncoding RNA molecules with important regulatory functions whose role in regulating natural killer (NK) cell biology is not well defined. Here, we show that miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. Over-expression of miR-155 enhanced induction of IFN-γ by IL-12 and IL-18 or CD16 stimulation, whereas knockdown of miR-155 or its disruption suppressed IFN-γ induction in monokine and/or CD16-stimulated NK cells. These effects on the regulation of NK cell IFN-γ expression were found to be mediated at least in part via miR-155's direct effects on the inositol phosphatase SHIP1. Consistent with this, we observed that modulation of miR-155 overrides IL-12 and IL-18-mediated regulation of SHIP1 expression in NK cells. Collectively, our data indicate that miR-155 expression is regulated by stimuli that strongly induce IFN-γ in NK cells such as IL-12, IL-18, and CD16 activation, and that miR-155 functions as a positive regulator of IFN-γ production in human NK cells, at least in part via down-regulating SHIP1. These findings may have clinical relevance for targeting miR-155 in neoplastic disease.
  Blood 02/2012; 119(15):3478-85. · 9.90 Impact Factor
• Article: Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies.

  Eugenio Gaudio, Riccardo Spizzo, Francesco Paduano, Zhenghua Luo, Alexey Efanov, Alexey Palamarchuk, Amanda S Leber, Mohamed Kaou, Nicola Zanesi, Arianna Bottoni, Stefan Costinean, Laura Z Rassenti, Tatsuya Nakamura, Thomas J Kipps, Rami I Aqeilan, Yuri Pekarsky, Francesco Trapasso, Carlo M Croce
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  ABSTRACT: The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.
  Blood 11/2011; 119(1):180-7. · 9.90 Impact Factor
• Article: Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer.

  Esmerina Tili, Jean-Jacques Michaille, Dorothee Wernicke, Hansjuerg Alder, Stefan Costinean, Stefano Volinia, Carlo M Croce
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  ABSTRACT: Infection-driven inflammation has been implicated in the pathogenesis of ~15-20% of human tumors. Expression of microRNA-155 (miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecular mechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequency of HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiency of DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressor genes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that the development of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.
  Proceedings of the National Academy of Sciences 03/2011; 108(12):4908-13. · 9.68 Impact Factor
• Source

  Available from: PubMed Central

  Article: Common fragile site tumor suppressor genes and corresponding mouse models of cancer.

  Alessandra Drusco, Yuri Pekarsky, Stefan Costinean, Anna Antenucci, Laura Conti, Stefano Volinia, Rami I Aqeilan, Kay Huebner, Nicola Zanesi
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  ABSTRACT: Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS.
  Journal of Biomedicine and Biotechnology 01/2011; 2011:984505. · 2.44 Impact Factor
• Source

  Available from: Anna Bratasz

  Article: Loss of metallothionein predisposes mice to diethylnitrosamine-induced hepatocarcinogenesis by activating NF-kappaB target genes.

  Sarmila Majumder, Satavisha Roy, Thomas Kaffenberger, Bo Wang, Stefan Costinean, Wendy Frankel, Anna Bratasz, Periannan Kuppusamy, Tsonwin Hai, Kalpana Ghoshal, Samson T Jacob
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  ABSTRACT: Metallothioneins (MT) are potent scavengers of free radicals that are silenced in primary hepatocellular carcinomas (HCC) of human and rodent origin. To examine whether loss of MT promotes hepatocarcinogenesis, male Mt-1 and Mt-2 double knockout (MTKO) and wild-type (WT) mice were exposed to diethylnitrosamine (DEN) and induction of HCC was monitored at 23 and 33 weeks. The size and number of liver tumors, the ratio between liver and body weight, and liver damage were markedly elevated in the MTKO mice at both time points compared with the WT mice. At 23 weeks, MTKO mice developed HCC whereas WT mice developed only preneoplastic nodules suggesting that loss of MT accelerates hepatocarcinogenesis. MTKO tumors also exhibited higher superoxide anion levels. Although NF-κB activity increased in the liver nuclear extracts of both genotypes after DEN exposure, the complex formed in MTKO mice was predominantly p50/65 heterodimer (transcriptional activator) as opposed to p50 homodimer (transcriptional repressor) in WT mice. Phosphorylation of p65 at Ser276 causing its activation was also significantly augmented in DEN-exposed MTKO livers. NF-κB targets that include early growth response genes and proinflammatory cytokines were significantly upregulated in MTKO mice. Concurrently, there was a remarkable increase (∼100-fold) in Pai-1 expression; significant increase in c-Jun, c-Fos, c-Myc, Ets2, and ATF3 expressions; and growth factor signaling that probably contributed to the increased tumor growth in MTKO mice. Taken together, these results demonstrate that MTs protect mice from hepatocarcinogen-induced liver damage and carcinogenesis, underscoring their potential therapeutic application against hepatocellular cancer.
  Cancer Research 12/2010; 70(24):10265-76. · 7.86 Impact Factor
• Article: Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features.

  Gulnur Guler, Cigdem Himmetoglu, Rafael E Jimenez, Susan M Geyer, Wenle P Wang, Stefan Costinean, Robert T Pilarski, Carl Morrison, Dinc Suren, Jianhua Liu, Jingchun Chen, Jyoti Kamal, Charles L Shapiro, Kay Huebner
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  ABSTRACT: Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.
  Breast Cancer Research and Treatment 11/2010; 129(2):421-32. · 4.43 Impact Factor
• Article: Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression.

  Urmila Santanam, Nicola Zanesi, Alexey Efanov, Stefan Costinean, Alexey Palamarchuk, John P Hagan, Stefano Volinia, Hansjuerg Alder, Laura Rassenti, Thomas Kipps, Carlo M Croce, Yuri Pekarsky
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  ABSTRACT: B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V(H)) and indolent (showing low ZAP-70 expression and mutated IgH V(H)). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19(+) B cells. To study the role of miR-29 in B-CLL, we generated Emu-miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5(+) population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5(+) B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5(+) B-cell population to approximately 100%. Of 20 Emu-miR-29 transgenic mice followed to 24-26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.
  Proceedings of the National Academy of Sciences 07/2010; 107(27):12210-5. · 9.68 Impact Factor
• Article: Reprogramming of miRNA networks in cancer and leukemia.

  Stefano Volinia, Marco Galasso, Stefan Costinean, Luca Tagliavini, Giacomo Gamberoni, Alessandra Drusco, Jlenia Marchesini, Nicoletta Mascellani, Maria Elena Sana, Ramzey Abu Jarour, [......], Anne Dejean, Nicola Zanesi, Simona Rossi, George A Calin, Chang-Gong Liu, Jeff Palatini, Massimo Negrini, Andrea Vecchione, Anne Rosenberg, Carlo M Croce
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  ABSTRACT: We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.
  Genome Research 05/2010; 20(5):589-99. · 13.61 Impact Factor
• Article: Modulation of mismatch repair and genomic stability by miR-155.

  Nicola Valeri, Pierluigi Gasparini, Muller Fabbri, Chiara Braconi, Angelo Veronese, Francesca Lovat, Brett Adair, Ivan Vannini, Francesca Fanini, Arianna Bottoni, [......], Roberta Gafa, Federica Calore, Manuela Ferracin, Giovanni Lanza, Stefano Volinia, Massimo Negrini, Michael A McIlhatton, Dino Amadori, Richard Fishel, Carlo M Croce
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  ABSTRACT: Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10-40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
  Proceedings of the National Academy of Sciences 03/2010; 107(15):6982-7. · 9.68 Impact Factor
• Article: miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation.

  Michela Garofalo, Gianpiero Di Leva, Giulia Romano, Gerard Nuovo, Sung-Suk Suh, Apollinaire Ngankeu, Cristian Taccioli, Flavia Pichiorri, Hansjuerg Alder, Paola Secchiero, Pierluigi Gasparini, Arianna Gonelli, Stefan Costinean, Mario Acunzo, Gerolama Condorelli, Carlo Maria Croce
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  ABSTRACT: Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.
  Cancer cell 12/2009; 16(6):498-509. · 25.29 Impact Factor
• Article: Karyotype-specific microRNA signature in chronic lymphocytic leukemia.

  Rosa Visone, Laura Z Rassenti, Angelo Veronese, Cristian Taccioli, Stefan Costinean, Baltazar D Aguda, Stefano Volinia, Manuela Ferracin, Jeff Palatini, Veronica Balatti, Hansjuerg Alder, Massimo Negrini, Thomas J Kipps, Carlo M Croce
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  ABSTRACT: Chromosomal abnormalities, immunoglobulin heavy chain variable-region (IGHV) gene mutation status, and zeta-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.
  Blood 09/2009; 114(18):3872-9. · 9.90 Impact Factor
• Article: Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice.

  Stefan Costinean, Sukhinder K Sandhu, Irene M Pedersen, Esmerina Tili, Rossana Trotta, Danilo Perrotti, David Ciarlariello, Paolo Neviani, Jason Harb, Lauren Rachel Kauffman, Aaditya Shidham, Carlo Maria Croce
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  ABSTRACT: We showed that Emicro-MiR-155 transgenic mice develop acute lymphoblastic leukemia/high-grade lymphoma. Most of these leukemias start at approximately 9 months irrespective of the mouse strain. They are preceded by a polyclonal pre-B-cell proliferation, have variable clinical presentation, are transplantable, and develop oligo/monoclonal expansion. In this study, we show that in these transgenic mice the B-cell precursors have the highest MiR-155 transgene expression and are at the origin of the leukemias. We determine that Src homology 2 domain-containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein beta (C/EBPbeta), 2 important regulators of the interleukin-6 signaling pathway, are direct targets of MiR-155 and become gradually more down-regulated in the leukemic than in the preleukemic mice. We hypothesize that miR-155, by down-modulating Ship and C/EBPbeta, initiates a chain of events that leads to the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma.
  Blood 07/2009; 114(7):1374-82. · 9.90 Impact Factor
• Article: Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2gamma expression levels correlate with basal phenotype in breast cancer.

  Gulnur Guler, Kay Huebner, Cigdem Himmetoglu, Rafael E Jimenez, Stefan Costinean, Stefano Volinia, Robert T Pilarski, Mutlu Hayran, Charles L Shapiro
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  ABSTRACT: The expression of fragile histidine triad protein (Fhit) and WW domain-containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2alpha and AP2gamma, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) and their associations with breast cancer phenotypes. Tissue microarrays constructed from 837 breast cancer blocks were immunostained. Expression in >10% of tumor cells was considered positive for cytoplasmic CK5/6, membranous EGFR, and nuclear AP2alpha and AP2gamma. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR, and HER-2 status of tumors was derived from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods. Triple-negative tumors had more frequent expression of EGFR, CK5/6 (P < .001), and AP2gamma (P = .003) and more frequent loss of Fhit and Wwox (P < .001), and an inverse correlation was observed between Fhit, Wwox expression and EGFR, ER, and PR expression (P < .001). Reduced Fhit expression was more common in HER-2-positive and AP2gamma-positive cases (P < .001 and P = .002, respectively). There was a direct correlation noted between Fhit and Wwox (P < .001) and a borderline positive relation between AP2alpha and AP2gamma (P = .054). The results from this investigation suggested that reduced expression levels of Fhit, Wwox, and nuclear AP2gamma have roles in the pathogenesis of basal-like differentiation in breast cancer. Alteration in the expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in breast cancer 1 (BRCA1)-deficient cancers. Thus, DNA damage response checkpoint proteins may be targets for treatment.
  Cancer 02/2009; 115(4):899-908. · 4.77 Impact Factor
• Article: MicroRNAs, the immune system and rheumatic disease.

  Esmerina Tili, Jean-Jacques Michaille, Stefan Costinean, Carlo M Croce
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  ABSTRACT: MicroRNAs (miRNAs) are short noncoding RNA molecules that modulate the expression of multiple target genes at the post-transcriptional level and are implicated in a wide array of cellular and developmental processes. In hematopoietic cells, miRNA levels are dynamically regulated during lineage differentiation and also during the course of the immune response. Mouse models have provided good evidence for miRNAs being key players in the establishment of hematopoietic lineages. Furthermore, miRNA-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response to a wide range of pathogens, spontaneously emerging tumors, and autoimmune cells. Deregulation of hematopoietic-specific miRNA expression results in defects in both central and peripheral tolerance, hematopoietic malignancies, and sometimes both. Abnormal expression of miRNAs-which is implicated in inflammation-has also been found in patients with rheumatoid arthritis. These findings identify miRNAs as critical targets for immunomodulatory drug development.
  Nature Clinical Practice Rheumatology 09/2008; 4(10):534-41. · 5.85 Impact Factor